Orbital inflammation is the most common presentation of VEXAS, with any orbital structure potentially affected. Non-sight-threatening and uncomplicated anterior non-granulomatous uveitis and anterior diffuse scleritis follow in frequency, along with episcleritis. Ophthalmic involvement was significantly associated with relapsing polychondritis (p = 0.014), with an increased chance of a fatal outcome (RR 5.87, p = 0.016) and independently predicts a higher mortality rate (OR 3.72, p = 0.026). Treatment of ophthalmic involvement showed full or partial response to glucocorticosteroids alone in 66.7% of cases. Ophthalmic involvement is common in VEXAS syndrome and signals a poorer prognosis in terms of mortality, highlighting the need for close monitoring.

Systemic sclerosis (SSc) is a disease in which malfunctioning immune cells lead to the formation of autoantibodies that damage blood vessels and body tissues. Fibrosis then develops in the affected organs. Its complex pathogenesis involves multiple immune and stromal cell types, soluble mediators, and dysregulated tissue repair, resulting in heterogeneous clinical manifestations and poor prognosis. Current disease-modifying therapies provide only modest benefits, often slowing but rarely reversing disease progression, and are associated with considerable adverse effects. These limitations have spurred the development of cell-based therapeutic strategies aimed at restoring immune tolerance and promoting tissue repair. In this review, we summarize recent advances in hematopoietic stem cell transplantation, mesenchymal stem cell therapy, and adoptive regulatory T cell transfer and highlight the emerging role of chimeric antigen receptor (CAR)-T cell therapy as a transformative approach for SSc. Collectively, these evolving strategies hold the potential to improve survival, achieve durable remissions, and significantly enhance quality of life for patients with SSc.

IntroductionRecurrent febrile episodes account for one of the most frequent symptoms observed in Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic (VEXAS) syndrome and a key target for therapeutic intervention. Therefore, this study aims at investigating the association between recurrent febrile episodes and specific clinical manifestations, mortality and response to treatment.MethodsData were obtained from the international AutoInflammatory Disease Alliance (AIDA) Network registry and analyzed using a Bayesian statistical approach. Posterior probabilities [P(β)] were calculated to assess the likelihood that fever was associated with clinical, laboratory, genetic, and therapeutic features.ResultsIn total, 87 VEXAS patients were enrolled, 65 (74.7%) of whom suffered from recurrent fever episodes. Fever episodes showed a significant association with patients’ mortality [P(β): 99.41%], as well as with major inflammatory organ involvement, including cardiac [P(β): 99.99%], lung [P(β): 99.98%], and gastrointestinal [P(β): 97.5%] involvement. The occurrence of recurrent fever episodes was associated with a negligible probability of both complete response and treatment failure [P(β) <2.5%], instead favoring a partial response [P(β) >97.5%] to conventional disease modifying anti-rheumatic drugs, Janus Kinases inhibitors, and tocilizumab. For temperatures exceeding 40 °C, using anti-interleukin-1 agents was associated with a high probability of treatment failure [P(β): 99.3%].Conclusionsfebrile episodes are associated with more severe pattern of organ involvement and, accordingly, to death. Furthermore, febrile episodes could correlate with differential therapeutic responsiveness, thereby potentially serving as a valuable marker to guide the treatment strategies in VEXAS patients.

ABSTRACT Background Whether Takayasu arteritis (TAK) and giant cell arteritis (GCA), the most common forms of large‐vessel vasculitis (LVV), are distinct clinical entities or different manifestations of the same disease is an ongoing debate. This study analyzes and compares the clinical manifestations, imaging characteristics, and diagnostic and therapeutic features of TAK and GCA in a longitudinal cohort of patients recruited from three Italian centers. Methods The study population consisted of 59 patients with TAK and 37 with GCA, including 7 with cranial‐GCA (C‐GCA) and 30 with large vessel‐GCA (LV‐GCA), all diagnosed between January 2014 and November 2025. Most (72%) were followed up for at least 60 months. Results In TAK patients, the time to diagnosis following the onset of symptoms was longer ( p = 0.025), the prevalence of females higher ( p = 0.001), and the presence at diagnosis of constitutional symptoms ( p < 0.001), cardiovascular signs ( p < 0.001), renal ( p = 0.006) and dermatologic involvement ( p = 0.040) more frequent than in GCA patients. In GCA patients, the sex distribution was equal. However, in addition to the cranial and constitutional symptoms associated with the cranial and large vessel forms of the disease, respectively, the prevalence of polymyalgia rheumatica ( p < 0.001), hypertension ( p < 0.001), diabetes mellitus ( p = 0.003), and chronic liver disease ( p = 0.02) was higher in GCA than in TAK patients. Vascular involvement was observed in both groups, with participation of the axillary artery more frequent in GCA patients ( p = 0.02). Additionally, involvement of the aortic arch ( p = 0.009), mesenteric ( p = 0.004), and renal ( p < 0.001) arteries was more frequent in TAK patients. Glucocorticoids were administered at a higher dose ( p < 0.001) and combined more frequently with immunosuppressants in TAK patients. Among relapsing/refractory GCA patients, 50% received tocilizumab as second‐line treatment. The two groups did not significantly differ concerning long‐term remission, but relapse was more frequent in TAK patients. Conclusions Despite their phenotypic similarities, TAK and GCA differ in their epidemiological and genetic features and, to a lesser extent, in their clinical manifestations, arterial involvement, and response to therapy. Our data therefore indicate that TAK and GCA are clinically distinct, requiring disease‐specific approaches in their diagnosis and management.

ObjectivesTo evaluate the therapeutic management of patients with active adult-onset Still’s disease (AOSD) in a multicentre real-world setting and to provide and compare current real-world treatment strategies with existing recent international recommendations.MethodsFrom January 2022 to December 2023, 173 consecutive patients with active AOSD attending centres participating in the Gruppo Italiano di Ricerca in Reumatologia Clinica e Sperimentale (GIRRCS) AOSD research study group were prospectively enrolled. Demographic, clinical, and laboratory data were collected, and therapeutic strategies prescribed by the treating physicians were systematically recorded. Factors associated with the administration of biologic disease-modifying antirheumatic drugs (bDMARDs), including IL-1 and IL-6 inhibitors, were analysed.ResultsGlucocorticoids were administered in 97.7% of patients. Conventional synthetic DMARDs were prescribed in 58.8% of cases, mainly methotrexate and cyclosporin A. Overall, 43.3% of patients received bDMARDs, predominantly IL-1 and IL-6 inhibitors. Specifically, 33.5% were treated with IL-1 inhibitors, 5.8% with IL-6 inhibitors, and 4.0% with tumour necrosis factor inhibitors. After three months of treatment, 86.7% of patients achieved clinical inactive disease as assessed by the treating physician. Comparing recorded treatment strategies with international recommendations, no compliance was found regarding the use of glucocorticoids, which are recommended to be markedly limited or avoided, and early administration of bDMARDs, which were administered within 3 months in a minority of patients.ConclusionsThis multicentre real-world study outlines current therapeutic approaches for patients with active AOSD and highlights a gap between international treatment recommendations and clinical practice, underscoring the need for further studies to optimize patient management.

Cardiovascular (CV) events (CVE) are a leading cause of morbidity and mortality in systemic lupus erythematosus (SLE), and affected patients display a two- to three-fold higher risk than the general population. This increased CV risk remains underestimated by traditional CV risk algorithms, which do not account for SLE-specific drivers of accelerated atherosclerosis. The aim of this review is to examine key biomarkers and immune-mediated pathways involved in immune dysregulation and vascular injury. By comparing their contribution to SLE pathogenesis and atherosclerotic plaque development, we have highlighted biomarkers that may be incorporated into more accurate, SLE-specific CV risk assessment tools.

Objectives To evaluate whether early canakinumab initiation may provide treatment advantages in Still’s disease (SD) patients, particularly in terms of therapy discontinuation due to long-term disease remission, glucocorticoid sparing effect, and increase in the frequency of monocyclic disease course rather than a polycyclic or chronic articular pattern. Methods SD patients treated with canakinumab were grouped according to time between disease onset and canakinumab initiation (≤3 months vs. >3 months). Patients were enrolled from the international AutoInflammatory Disease Alliance (AIDA) Network registry for SD. Results Overall, 190 patients were enrolled, 35 (19%) treated with canakinumab within three months from SD onset and 155 (82%) starting canakinumab later. Glucocorticoids use decreased more rapidly in patients receiving canakinumab within 3 months from SD onset than among patients treated later, with reductions of 50% vs 6% at month 3 (p=0.0001), and 75% vs 32% at month 6 (p=0.004). In logistic regression analysis, canakinumab initiation within 3 months from disease onset was significantly associated with treatment discontinuation due to long-term remission (OR 4.83, 95% CI 1.08-23.19; p=0.04). A monocyclic course occurred in 49% of patients starting canakinumab ≤3 months versus 8% starting later (p<0.0001). Starting canakinumab within 3 months from disease onset was significantly associated with a monocyclic disease course compared with the chronic-articular (RRR 4.43, 95% CI 1.12-17.60; p=0.034) and polycyclic courses (RRR 8.97, 95% CI 1.29-62.3; p=0.03). Conclusions Early canakinumab initiation is associated with treatment discontinuation due to long-term remission and appears linked to a greater frequency of a monocyclic disease course.

OBJECTIVES:The aim of this cross-sectional study was to investigate the prevalence and associated barriers of non-adherence to therapy (NAT) in a large cohort of Italian patients with systemic lupus erythematosus (SLE). METHODS:This multicentre cross-sectional study included 432 adult SLE patients. Adherence to therapy (AT) was assessed through the Medication Adherence Self-Report Inventory (MASRI) and adherence rates <80% were considered non-adherent. Psychological distress was evaluated via the Hospital Anxiety and Depression Scale (HADS). Barriers to AT were identified using a 32-item questionnaire addressing patient-, therapy-, socioeconomic-, and healthcare-related factors. Statistical analyses were performed to identify associations with NAT. RESULTS:NAT was observed in 38% of patients and was significantly associated with younger age (p<0.001) and higher HADS scores (p<0.001). Common patient-related barriers included forgetfulness (OR=11.56, p<0.001), daily routine changes (OR=5.29, p<0.001), and perceived hassle (OR=4.85, p<0.001). Key therapy-related barriers included fear (OR=29.15, p<0.001) and suffering (OR=5.73, p<0.001) side effects. Among socioeconomic barriers, only cost concerns were associated with NAT (OR=3.75, p=0.002). Healthcare system-related issues such as long waiting list (OR=2.01, p=0.003), divergent medical opinions (OR=2.10, p=0.001), and prescribed delay (OR=2.36, p=0.004) were more frequent in NAT patients. ROC curve analysis revealed an association between age ≤48 years and the presence of NAT and related behavioural barriers. CONCLUSIONS:NAT is prevalent among Italian SLE patients and is driven by a combination of modifiable patient, therapy, and healthcare system barriers. Younger patients are at high risk of NAT due to behavioural and psychosocial barriers. Age-targeted interventions are needed to enhance adherence and outcomes.

Background:A substantial overlap in demographic, clinical, and laboratory features can complicate the differential diagnosis between Schnitzler's syndrome and VEXAS syndrome. The present study was undertaken to identify clinical and laboratory parameters that should raise suspicion for VEXAS syndrome among patients previously diagnosed with, or under evaluation for, Schnitzler's syndrome. Methods:Data from male-only patients with Schnitzler's syndrome or VEXAS syndrome were obtained from international AIDA Network registries. Subjects with Schnitzler's syndrome were compared to VEXAS patients with urticarial skin manifestations resembling cutaneous features typically observed in Schnitzler's syndrome. Results:A total of 19 VEXAS patients and 18 patients with Schnitzler's syndrome were enrolled. At univariate binary logistic regression, the diagnosis of VEXAS syndrome was associated with the age at disease onset (OR = 1.08, 95% CI. 1.01-1.16, p = 0.02), hemoglobin levels (OR = 0.44, 95% CI. 0.26-0.77, p = 0.003), anemia (OR = 13.9, 95% CI. 3.4-5.7, p = 0.02), leucocytosis (OR = 0.04, 95% CI. 0.06-0.22, p < 0.001), lymphadenopathy (OR = 7.8, 95% CI. 1.41-45.4, p = 0.02), and thrombocytopenia (OR = 13.5, 95% CI. 1.47-123.7, p = 0.02). In the multivariable logistic regression analysis with the stepwise forward selection approach, the diagnosis of VEXAS syndrome was significantly associated with the age at disease onset (OR: 1.13, 95% CI: 1.02-1.30, p = 0.04) and the presence of lymphadenopathy (OR: 67.49, 95% CI: 5.36-3284.89, p = 0.007), while thrombocytopenia showed a trend toward statistical significance (OR: 12.02, 95% CI: 1.07-315.86, p = 0.06). Conclusions:Patients with lymphadenopathy, thrombocytopenia, anemia, particularly in older age and in the absence of leucocytosis, are more likely to be affected by VEXAS syndrome rather than Schnitzler's syndrome.

ObjectivesThis study aims to explore the application of machine learning techniques in assessing macrophage activation syndrome (MAS) in Still’s disease.MethodsA multicenter, observational, prospective study was conducted, including patients with Still’s disease enrolled in the Gruppo Italiano di Ricerca in Reumatologia Clinica e Sperimentale (GIRRCS) AOSD Study Group and the AutoInflammatory Disease Alliance (AIDA) Network Still’s Disease Registry.ResultsA total of 737 patients (age: 35.5 ± 17.8, male sex: 44.7%) with Still’s disease were assessed; 11.4% were affected by MAS, and 3% had a poor prognosis. First, random forest imputation was applied to the original dataset. Subsequently, a machine-learning-driven assessment was developed to explore MAS occurrence. Collectively, regression models, an exploration decision tree, and a random forest were applied, suggesting the importance of ferritin, age, C-reactive protein (CRP), and systemic score. A logistic regression model accounting for data leakage concerns was then generated using these variables, and missing values were imputed using random forest imputation. This analysis supported the role of the selected variables, which were further combined across different clinical scenarios to estimate the probability of MAS. The highest risk of MAS was estimated for patients simultaneously characterized by age ≥ 45 years, ferritin ≥ 4,178.10 ng/mL, CRP ≥ 27.15 mg/L, and a systemic score ≥ 7, corresponding to a 34.7% probability of MAS, as well as for those characterized by ferritin ≥ 4,178.10 ng/mL, CRP ≥ 27.15 mg/L, and systemic score ≥ 7, corresponding to a 33.5% probability of MAS.ConclusionsA machine-learning-driven prediction of MAS was explored in Still’s disease, highlighting the importance of age of onset, hyperferritinaemia, increased CRP, and multiorgan involvement. A combination of these features may suggest a clinician-friendly algorithm for stratifying the probability of MAS during Still’s disease.

BACKGROUND:VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) syndrome is an acquired autoinflammatory disorder characterized by severe chronic inflammation and an increased occurrence of hematologic neoplasms. Although chronic inflammation is a well-established risk factor for cancer, the specific contribution of UBA1 gene mutations to tumorigenesis remains unclear. Therefore, this study aimed to evaluate the overall cancer risk in patients with VEXAS syndrome, including both hematologic and non-hematologic neoplasms. METHODS:The relative risk (RR) of cancer was compared between VEXAS patients and a control cohort comprising individuals with Still's disease, Behçet's disease, and Schnitzler's syndrome. Logistic regression analysis was performed to identify variables potentially associated with cancer development. Patient's data were drawn from the International AutoInflammatory Disease Alliance (AIDA) Network registries for VEXAS syndrome, Still's disease, Behçet's disease, and Schnitzler's syndrome. RESULTS:Ninety-six VEXAS patients and 2181 controls were enrolled. To minimize selection bias, only subjects aged >60 years were included, yielding 90 and 174 individuals in the exposed and control groups, respectively. The overall RR for cancer in VEXAS patients was 1.93 (95 % Confidence Interval [C.I.] 1.03-3.60, p = 0.036). Logistic regression analysis identified associations between cancer development and relapsing polychondritis (RR = 2.67, 95 %C.I. 1.22-10.64, p = 0.01), the p.Met41Thr mutation (RR = 3.33, 95 %C.I. 1.29-17.33, p = 0.02), elevated serum erythrocyte sedimentation rate (RR = 1.02, 95 %C.I. 1.01-1.05 p = 0.01), and lactate dehydrogenase (RR = 1.02, 95 %C.I. 1.01-1.07 p = 0.04) levels outside of flares. CONCLUSIONS:VEXAS patients exhibit a significantly increased risk of both hematologic and non-hematologic malignancies compared with controls, particularly among those with RP, p.Met41Thr mutation, and persistent systemic inflammation.

ObjectiveThe primary aim of this study was to assess, in Still’s disease, whether the employment of canakinumab at a strictly on-label dose may increase the likelihood of treatment discontinuation due to study-defined long-term remission (LTR), compared with patients receiving lower doses.MethodsPatients were drawn from the international Autoinflammatory Disease Alliance (AIDA) Network registry dedicated to Still’s disease and stratified based on the starting canakinumab dose: the on-label group received either 300 mg every 4 weeks or 150 mg every 4 weeks (corresponding to 4 mg/kg), while the underdosed group received 150 mg every 4 weeks (corresponding to a dose not exceeding 3.5 mg/kg). Bayesian regression models were implemented to estimate the probability of achieving long-term remission with subsequent canakinumab withdrawal in the two groups, as well as the mean differences in probabilities and posterior probabilities indicating whether the on-label group was superior in achieving the endpoint.ResultsIn total, 131 patients (16.7%) were enrolled, 81 (61.8%) receiving the on-label posology and 50 (38.2%) the underdosed posology. The estimated marginal posterior probability of canakinumab discontinuation due to LTR was 19% (CrI 7.5%–34.6%) in the on-label group and 3.9% (CrI 0.7%–15.2%) in the underdosed group, yielding a mean difference of 15.1% (CrI 1.4%–31.4%) and a posterior probability of 98.4%. This difference remained credible, with posterior probabilities ranging from 97.9% to 99.6%, irrespective of disease course or age at disease onset.ConclusionOn-label canakinumab dosing appears to increase the likelihood of study-defined LTR with subsequent treatment discontinuation, compared with underdosed treatment strategies.

OBJECTIVE:We previously identified, using a synthetic peptide, namely peptide 4.33 (p4.33), a subgroup of anti-CENP-A antibodies (Abs) recognizing an epitope shared between the CENP-A region spanning amino acids 1-17 (Ap1-17) and the E2 component of the mitochondrial pyruvate dehydrogenase complex (PDC-E2), the major mitochondrial target autoantigen in primary biliary cholangitis (PBC). Here, we evaluated whether anti-p4.33 Ab positivity may be associates with a higher prevalence of antimitochondrial Ab (AMA) in systemic sclerosis (SSc) patients. METHODS:Serum samples from 145 anti-CENPpos SSc patients were tested for anti-CENP-A, -Ap1-17, and -p4.33 Abs by ELISA. Subsequently, 32 anti-Ap1-17pos/p4.33pos and 32 anti-Ap1-17pos/p4.33neg were randomly selected and tested for AMA by immunoblotting. RESULTS:Of 145 anti-CENPpos patients, 128 (88.2%) were anti-CENP-Apos patients, of which 103 (80.5%) were positive for anti-Ap1-17 Abs and 66 (51.6%) were positive for anti-p4.33 Abs. Of 32 selected anti-Ap1-17pos/p4.33pos patients, 15 (46.9%) were also positive for AMA targeting PDC-E2 and/or the branched chain 2-oxo acid dehydrogenase complex (BCOADC-E2). In the Ap1-17pos/p4.33neg group, AMA were detected in only two patients (6.25%). AMA positivity was statistically different between groups. Anti-p4.33 Ab levels were directly associated more than anti-Ap1-17 Ab levels with AMA levels. Sequence homology analyses demonstrated that anti-p4.33 Abs recognize an epitope (kPsaP) strongly overlapping with those of Ap1-17, PDC-E2, and BCOADC-E2, also expressed by viral and bacterial proteins. CONCLUSIONS:Anti-p4.33 Abs may be a useful biomarker to define a subset of SSc patients with a higher prevalence of AMA. Our findings also support the hypothesis that pathogens can trigger autoimmunity.

OBJECTIVES:Raynaud's phenomenon (RP) can be induced by stress and environmental factors, occurring as a primary disease (pRP) or associated with connective tissue disease. RP is seen in more than 95% of patients with systemic sclerosis (SSc) and may precede its diagnosis by several years. Accordingly, there is a clear need to identify those patients with RP who will eventually develop connective tissue disease, including SSc. The aim of this case-control study was to assess the association of SSc-RP versus pRP with respect to environmental factors, lifestyle habits, and clinical setting. METHODS:A questionnaire was used to collect current data from 180 patients with SSc-RP and 103 with pRP. Statistical analyses were performed to identify possible risk factors for SSc-RP. RESULTS:SSc-RP was found to be inversely associated with living in urban area (OR=0.37; p<0.001), computer use (OR=0.38, p<0.001), contraceptive use (OR=0.32; p=0.017), habitual alcohol use (OR=0.35; p=0.029), and hepatitis B virus vaccine (OR=0.09; p=0.011),while it was directly associated to cold sensitivity (OR=3.48; p=0.001), lower quality of life (OR=2.69; p<0.001), finger pain (OR=3.03; p<0.001) and autoimmune hypothyroidism (OR=3.62; p=0.007). All associations were supported by either multivariate and/or multivariable analyses. CONCLUSIONS:This study revealed differences in lifestyle and preventive health behaviours between SSc-RP and pRP, and also suggests that patients with pRP and autoimmune hypothyroidism should be strictly monitored for any clinical changes that may indicate SSc onset. Further investigations are needed to prospectively evaluate autoimmune hypothyroidism as a predisposing condition for SSc-RP.

Entheses are specialized tissues that connect ligaments and tendons to the bone surface and are frequently involved in seronegative spondyloarthritis. Enthesitis can also be detected in patients with metabolic disorders (MD), regardless of baseline autoimmune rheumatic disease, posing real diagnostic challenges. The present review discusses the pathophysiology of enthesitis and metabolic-associated enthesitis, the clinical relevance of metabolic disorders on enthesitis-related outcomes, diagnostic challenges for adequate differential diagnosis, and possible therapeutic strategies to improve clinical outcomes. PubMed/MEDLINE and the Cochrane Library were searched for original articles, systematic reviews, and meta-analyses. References were screened according to a hierarchical analysis of studies by title, abstract, and full text, collected, presented, and discussed. Metabolic-associated enthesitis is attributable to mechanical stress/overload due to weight excess typically observed in metabolic disorders (MD), such as overweight/obese comorbid patients, metabolic syndrome (MS), and type 2 diabetes (T2D). Interleukin 1β, 6, 17, 18, and 23 and tumor necrosis factor-α play a crucial role in initiating and maintaining entheseal inflammation. Chronic hyperglycemia and insulin resistance lead to a vicious circle as they stimulate, upon activated, specialized T cells to produce these specific cytokines, thus maintaining entheseal inflammation chronically. MD is associated with more severe clinical presentation, worse response to pharmacological treatments, and poor entheseal outcomes also in patients with existing seronegative spondyloarthritis. Non-immune-mediated metabolic-associated enthesitis poses a real diagnostic challenge, possibly underestimating cases and potential misdiagnoses. From a therapeutic viewpoint, glucose control improvement and weight loss are associated with relevant amelioration of entheseal-related outcomes. Pharmacological and non-pharmacological interventions aiming to reduce body weight, improve glucose control and insulin sensitivity, and attenuate inflammation are desirable to achieve the therapeutic target. Glucagon-like peptide 1 receptor agonists and sodium-glucose co-transporter type 2 inhibitors, in add-on to non-steroidal anti-inflammatory drugs and immunomodulators when necessary, may have a therapeutic rationale in patients with metabolic-associated enthesitis. Awareness of metabolic-associated enthesitis is essential to improve the accuracy of differential diagnosis in patients with MD and prescribe appropriate therapeutic strategies. However, basic and clinical research is needed to understand the role of “antihyperglycemic” agents in better managing metabolic-associated enthesitis.

Key Clinical Message Pyoderma gangrenosum is a rare inflammatory ulcerative skin disease of unknown etiology. We report an image of a patient with pyoderma gangrenosum who presented right leg ulcers with violaceous margins, histologically characterized by mono‐ and polynuclear cell infiltrates. The patient was successfully treated with cyclosporin A.

The tumor microenvironment is a highly complex and dynamic mixture of cell types, including tumor, immune and endothelial cells (ECs), soluble factors (cytokines, chemokines, and growth factors), blood vessels and extracellular matrix. Within this complex network, ECs are not only relevant for controlling blood fluidity and permeability, and orchestrating tumor angiogenesis but also for regulating the antitumor immune response. Lining the luminal side of vessels, ECs check the passage of molecules into the tumor compartment, regulate cellular transmigration, and interact with both circulating pathogens and innate and adaptive immune cells. Thus, they represent a first-line defense system that participates in immune responses. Tumor-associated ECs are involved in T cell priming, activation, and proliferation by acting as semi-professional antigen presenting cells. Thus, targeting ECs may assist in improving antitumor immune cell functions. Moreover, tumor-associated ECs contribute to the development at the tumor site of tertiary lymphoid structures, which have recently been associated with enhanced response to immune checkpoint inhibitors (ICI). When compared to normal ECs, tumor-associated ECs are abnormal in terms of phenotype, genetic expression profile, and functions. They are characterized by high proliferative potential and the ability to activate immunosuppressive mechanisms that support tumor progression and metastatic dissemination. A complete phenotypic and functional characterization of tumor-associated ECs could be helpful to clarify their complex role within the tumor microenvironment and to identify EC specific drug targets to improve cancer therapy. The emerging therapeutic strategies based on the combination of anti-angiogenic treatments with immunotherapy strategies, including ICI, CAR T cells and bispecific antibodies aim to impact both ECs and immune cells to block angiogenesis and at the same time to increase recruitment and activation of effector cells within the tumor.

BACKGROUND:Activation of CD28 on multiple myeloma (MM) plasma cells, by binding to CD80 and CD86 on dendritic cells, decreases proteasome subunit expression in the tumor cells and thereby helps them evade being killed by CD8+ T cells. Understanding how CD28 activation leads to proteasome subunit downregulation is needed to design new MM therapies.METHODS:This study investigates the molecular pathway downstream of CD28 activation, using an in vitro model consisting of myeloma cell lines stimulated with anti-CD28-coated beads.RESULTS:We show that CD28 engagement on U266 and RPMI 8226 cells activates the PI3K/AKT pathway, reduces miR29b expression, increases the expression of DNA methyltransferase 3B (DNMT3B, a target of miR29b), and decreases immunoproteasome subunit expression. In vitro transfection of U266 and RPMI 8226 cells with a miR29b mimic downregulates the PI3K/AKT pathway and DNMT3B expression, restores proteasome subunit levels, and promotes myeloma cell killing by bone marrow CD8+ T cells from MM patients. Freshly purified bone marrow plasma cells (CD138+) from MM patients have lower miR29b and higher DNMT3B (mRNA and protein) than do cells from patients with monoclonal gammopathy of undetermined significance. Finally, in MM patients, high DNMT3B levels associate with shorter overall survival.CONCLUSIONS:Altogether, this study describes a novel molecular pathway in MM. This pathway starts from CD28 expressed on tumor plasma cells and, through the PI3K-miR29b-DNMT3B axis, leads to epigenetic silencing of immunoproteasome subunits, allowing MM plasma cells to elude immunosurveillance. This discovery has implications for the design of innovative miR29b-based therapies for MM.

Background: The initial phases of the COVID-19 pandemic posed a real need for clinicians to identify patients at risk of poor prognosis as soon as possible after hospital admission. Aims: The study aimed to assess the role of baseline anamnestic information, clinical parameters, instrumental examination, and serum biomarkers in predicting adverse outcomes of COVID-19 in a hospital setting of Internal Medicine. Methods: Fifty-two inpatients consecutively admitted to the Unit of Internal Medicine "Baccelli," Azienda Ospedaliero - Universitaria Policlinico of Bari (February 1 - May 31, 2021) due to confirmed COVID-19 were grouped into two categories based on the specific outcome: good prognosis (n=44), patients discharged at home after the acute phase of the infection; poor prognosis, a composite outcome of deaths and intensive care requirements (n=8). Data were extracted from medical records of patients who provided written informed consent to participate. Results: The two study groups had similar demographic, anthropometric, clinical, and radiological characteristics. Higher interleukin 6 (IL-6) levels and leucocyte count, and lower free triiodothyronine (fT(3)) levels were found in patients with poor than those with good prognosis. Higher IL-6 levels and leucocyte count, lower fT(3) concentration, and pre-existing hypercholesterolemia were independent risk factors of poor outcomes in our study population. A predicting risk score, built by assigning one point if fT(3) < 2 pg/mL, IL-6 >25 pg/mL, and leucocyte count >7,000 n/mm(3), revealed that patients totalizing at least 2 points by applying the predicting score had a considerably higher risk of poor prognosis than those scoring <2 points (OR 24.35 (1.32; 448), p = 0.03). The weight of pre-existing hypercholesterolemia did not change the risk estimation. Conclusion: Four specific baseline variables, one anamnestic (pre-existing hypercholesterolemia) and three laboratory parameters (leucocyte count, IL-6, and fT3), were significantly associated with poor prognosis as independent risk factors. To prevent adverse outcomes, the updated 4-point score could be useful in identifying at-risk patients, highlighting the need for specific trials to estimate the safety and efficacy of targeted treatments.

Pre-capillary pulmonary arterial hypertension (PAH) is hemodynamically characterized by a mean pulmonary arterial pressure (mPAP) ≥ 20 mmHg, pulmonary capillary wedge pressure (PAWP) ≤15 mmHg and pulmonary vascular resistance (PVR) > 2. PAH is classified in six clinical subgroups, including idiopathic PAH (IPAH) and PAH associated to connective tissue diseases (CTD-PAH), that will be the main object of this review. The aim is to compare these two PAH subgroups in terms of epidemiology, histological and pathogenic findings in an attempt to define disease-specific features, including autoimmunity, that may explain the heterogeneity of response to therapy between IPAH and CTD-PAH.